Long-Term Engraftment and Expansion of Tumor-Derived Memory T Cells Following the Implantation of Non-Disrupted Pieces of Human Lung Tumor into NOD-scid IL2Rγnull Mice

Abstract

Non-disrupted pieces of primary human lung tumor implanted into NOD-scid IL2Rγnull mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods with limited host-vs-graft interference. Human CD45+ tumor-associated leukocytes within the xenograft are predominantly CD3+ T cells with fewer CD138+ plasma cells. The effector memory T cells that had been shown to be quiescent in human lung tumor microenvironments can be activated in situ as determined by the production of human IFN-γ in response to exogenous IL-12. Plasma cells remain functional as evidenced by production of human Ig. Significant levels of human IFN-γ and Ig were detected in sera from xenograft-bearing mice for up to 9 wk postengraftment. Tumor-associated T cells were found to migrate from the microenvironment of the xenograft to the lung, liver, and primarily the spleen. At 8 wk postengraftment, a significant portion of cells isolated from the mouse spleens were found to be human CD45+ cells. The majority of CD45+ cells were CD3+ and expressed a phenotype consistent with an effector memory T cell, consisting of CD4+ or CD8+ T cells that were CD45RO+, CD44+, CD62L−, and CD25−. Following adoptive transfer into non-tumor bearing NOD-scid IL2Rγnull mice, these human T cells were found to expand in the spleen, produce IFN-γ, and maintain an effector memory phenotype. We conclude that the NOD-scid IL2Rγnull tumor xenograft model provides an opportunity to study tumor and tumor-stromal cell interactions in situ for prolonged periods.